Computational Chemistry to the Rescue: Modern Toolboxes for the Assignment of Complex Molecules by GIAO NMR Calculations

Abstract

The calculations of NMR properties of molecules using quantum chemical methods have deeply impacted several branches of organic chemistry. They are particularly important in structural or stereochemical assignments of organic compounds, with implications in total synthesis, stereoselective reactions, and natural products chemistry. In studying the evolution of the strategies developed to support (or reject) a structural proposal, it becomes clear that the most effective and accurate ones involve sophisticated procedures to correlate experimental and computational data. Owing to their relatively high mathematical complexity, such calculations (CP3, DP4, ANN-PRA) are often carried out using additional computational resources provided by the authors (such as applets or Excel files). This Minireview will cover the state-of-the-art of these toolboxes in the assignment of organic molecules, including mathematical definitions, updates, and discussion of relevant examples.

Application of Computational Chemical Shift Prediction Techniques to the Cereoanhydride Structure Problem—Carboxylate Complications

“…It was our goal to determine whether the correct structure of cereoanhydride could have been assigned on the basis of the originally reported NMR data in combination with quantum chemical computations. Our results demonstrate once again [6,7,8,9,10] the utility of NMR computations in the assignment of natural product structures, and highlight the complications of predicting chemical shifts for carboxylic acid-containing molecules.…”

“…3 Maximum absolute deviation. Deviations of <5 ppm ( 13 C) and <0.3 ppm ( 1 H) are generally considered acceptable [6,7,8,9,10]. …”

“…Unfortunately, the structures of many natural products have been misassigned initially, leading to frustration for chemists following up on these structures [4,5]. Computational chemistry, in particular NMR prediction using quantum chemical methods, can be used as a tool to facilitate confirmation, assignment, and reassignment of natural product structures [6,7,8,9,10] and therefore can be used to focus laboratory experiments on correct structures. While computational methods for predicting 1 H and 13 C chemical shifts are well established [6,7,8,9,10], these methods do not work without fail.…”

“…Computational chemistry, in particular NMR prediction using quantum chemical methods, can be used as a tool to facilitate confirmation, assignment, and reassignment of natural product structures [6,7,8,9,10] and therefore can be used to focus laboratory experiments on correct structures. While computational methods for predicting 1 H and 13 C chemical shifts are well established [6,7,8,9,10], these methods do not work without fail. We are particularly interested in cases where readily exchangeable protons affect 13 C chemical shifts, e.g., chemical shifts for carbons near to amines or carboxylic acids [11].…”

Computer‐Assisted 3D Structure Elucidation of Natural Products using Residual Dipolar Couplings

“…In the case of flexible molecules,t he determination of configuration is often not decoupled from the determination of the conformational space and therefore we should properly speak of 3D structural determination. [10] DFT predictions of chemical shifts have also proved to be an useful tool for relative configuration determination [11] and attempts to incorporate 13 Cchemical shift predictions,either DFT-based [12] or empirical ones, [13] as well as NOE data, [14] inside CASE programs have been reported. [8] In the case of scalar couplings,m ostly 3 J HH and 3 J HC are employed using suitable Karplus-like [9] relationships.N OE information is mostly used in aq ualitative way,a lthough in the last years fully quantitative NOE-based distances have been successfully employed.…”